It’s an old concept in migraine management that’s been given a new name in recent years: layering. “Conceptually, it’s nothing new,” said Jay Joshi, MD, DABA, DABA-PM, FABA-PM, CEO and medical director of National Pain Centers in Illinois. “This is how proper pain management really has been delivered for years, decades. This is natural thinking,” he explainedClinicians do it all the time with blood pressure and diabetes medicines, pointed out Dr. Joshi.

Recently, the available options for layering migraine care have expanded, especially with the approval of several calcitonin gene-related peptide (CGRP) monoclonal antibodies (mAbs). When CGRPs were approved, Dr. Joshi said, his offices were already offering onabotulinumtoxin-A (Botox), other pain medications, physical therapy, and other treatments. So adding the CGRPs, when indicated, was a natural next step. And ‘’when the CGRPs worked well, we could withdraw some other [medications],” he said.

No Official Guidelines on Layering Migraine Yet

While the concept of layering has been practiced for years, the array of ever-changing treatments can make treatment decisions difficult. As new treatments come out, ‘’It’s difficult to know how to use them in clinical practice,” said Matthew Robbins, MD, FAAN, FAHS, neurology residence program director and associate professor of neurology at Weill Cornell Medicine New York Presbyterian Hospital.

To help guide clinicians, the American Headache Society published a consensus statement in 2021.² The information in it, which Dr. Robbins coauthored, is not meant to serve as a practice guideline but rather of stepping stone to future guidelines. It addressed migraine treatments recently introduced.

Clinical Evidence for Combination Therapy

Although experts await more detailed studies on the newer treatments, some reports are pointing to their value and providing valuable information.

Today, because of the arrival of many new treatments, “we are able to make combination treatments work,” said Andrew M. Blumenfeld, MD, FAAN, FAHS, director of the Los Angeles Headache Center. Layering is crucial, he saidto get to what he terms “migraine freedom.” For different patients, he said, that means different things. “It doesn’t necessarily mean having no migraine; it may mean the freedom from enough pain to [be able to] go to work.”

With his colleagues, Dr. Blumenfeld published a retrospective, longitudinal chart review of 257 adults with chronic migraine (mean age 50, 82% women). All had previously been treated with medications such as topiramate (Topamax) and not obtained sufficient relief. They reported on the effects of placing the patients on onabotulinumtoxin-A (Botox) and then adding a CGRP.⁴

In addition, 45.1% of those patients had clinically meaningful improvement in migraine-related disability, defined as a 5 point or higher reduction in the MIDAS score (a questionnaire that measures how migraine affects a patient’s life) after 6 months.⁴

Adverse events occurred in 28% of patients, most often constipation, reported by 9%. No new safety signals were identified.⁴

When the layering worked, he often heard from patients that it changed their lives. The intensity of the headaches also reduced, he said.

In some cases, Dr. Blumenfeld said, he adds on a CGRP inhibitor such as rimegepant (Nurtec) to produce even more relief, reducing headache days per month further.

Obstacles to Layering Treatment

Despite the promises of adding new or different therapies onto existing, barriers and obstacles exist, experts agree.

“We’re bound by what the insurance company will allow,” Dr. Blumenfeld said. Some are allowing coverage of Botox and CGRP mAbs. It’s still only a handful, he said, but some companies have realized that ‘’it’s probably cheaper to pay for these drugs than pay for ER costs [when patients don’t get enough relief from covered medications].”

Prices without insurance vary, but a monthly supply of many of the CGRP inhibitors costs around $800.⁵

Practical Takeaways

For clinicians, such as those in primary care, who do not see headache in patients as often as do headache specialists, Dr. Blumenfeld had some practical advice. If clinicians are diagnosing a lot of tension headache, they are likely missing diagnoses of migraine.

As promising as some of the new and existing treatments are, he said, one fact remains sadly true: “We can control the disease with these medications, but we cannot cure it. But if we don’t control it, it will get worse.”


  1. FDA: New drug class employs novel mechanism for migraine treatment and prevention. January 29, 2019. Available at: Accessed April 16, 2023.
  2. Ailani J, Burch RC, Robbins MS; Board of Directors of the American Headache Society. The American Headache Society Consensus Statement: Update on integrating new migraine treatments into clinical practice. Headache. 2021;61(7):1021-1039. doi:10.1111/head.14153
  3. Sacco S, Lampl C, Amin FM, et al. European Headache Federation (EHF) consensus on the definition of effective treatment of a migraine attack and of triptan failure. J Headache Pain. 2022;23(1):133. Published 2022 Oct 12. doi:10.1186/s10194-022-01502-z
  4. Blumenfeld AM, Frishberg BM, Schim JD, et al. Real-world evidence for control of chronic migraine patients receiving CGRP monoclonal antibody therapy added to onabotulinumtoxinA: A retrospective chart review. Pain Ther. 2021;10(2):809-826. doi:10.1007/s40122-021-00264-x
  5. Shaffer C. CGRP inhibitors: uses, common brands, and safety info. April 5, 2022.